基于量子化学拓扑理论的RNA中静电多极距的理论和计算研究

Accurate atomic multipole moment can be used to calculate the atom-atom electrostatic interaction energy instead of atomic point charge. It is well known that the non-bonded interaction energy, in particular the electrostatic interaction energy, plays a crucial role in determining the structure of RNAs. As a result, improvements in a prediction method are critical to obtain more reliable RNA secondary structures. RNA secondary structure prediction algorithms and application study have been paid more and more attention by researchers. Currently some important prediction methods of RNA secondary structure are introduced, including the comparative sequence analysis method, the free energy minimization algorithm and the combinatorial algorithm. However, these methods cannot meet the higher requests for current RNA structure prediction day by day owing to their low average prediction accuracy. One of the very important reasons for these problems is that all these methods compute the atom-atom electrostatic interaction energy using atomic point charges. In this project, the theoretical and computational study of the multipolar electrostatics for RNAs based on Quantum Chemical Topology (QCT) has been put forward in order to increase the prediction accuracy of RNA secondary structure. The key point of QCT research is the atomic multipole moments, including dipole moment, quadrupole moment, octupole moment, and so on. The atom-atom electrostatic interaction energy is calculated using the atomic multipole moments instead of point charges. Ultimately, the prediction reliability of the new method is validated though predicting RNA secondary structures.

RNA中精确的原子多极距可以代替原子点电荷计算原子―原子静电作用能。如我们所知，RNA中非键作用能尤其是原子—原子静电作用能对整个分子的稳定结构起着至关重要的作用。因此，提高原子—原子静电作用能的计算精确度能够有效的改进RNA二级结构预测算法的预测结果。RNA二级结构的预测算法及其应用越来越多的受到研究人员的重视。目前，广泛用于预测RNA二级结构的方法主要包括基于比较序列分析方法，基于最小能的方法和组合优化算法。然而，这些算法日益满足不了当前RNA研究对结构预测的更高要求，预测精度还不够高。原因之一就是这些算法均通过原子点电荷计算RNA中原子—原子静电作用能。本项目拟基于量子化学拓扑(QCT)理论研究计算RNA中的原子多极距。QCT理论重点研究原子多极距，包括偶极距，四极距，八极距等，即原子—原子静电作用能通过原子多极距计算得到。最后通过预测RNA二级结构来检验该新的算法的预测结果。

由于RNA具有降解速度快，难以结晶等特点，通过X射线晶体衍射和NMR等实验方法测定RNA结构的花费成本高、时间长。RNA的计算模拟一直是分子力学方法中所面临的挑战之一。目前，用于RNA分子模拟的力场都是通过原子点电荷计算原子-原子静电相互作用能，其模拟结果不够准确。前期我们提出了用原子多极距代替点电荷来计算蛋白质分子模拟的力场中静电能项，并验证原子多极距能提高静电能项计算的精确度。在此基础上，本项目基于量子化学拓扑（QCT）理论重新设计了全新的用于RNA分子模拟的力场，即原子-原子静电作用能通过原子多极距，包括偶极矩，四极距，八极距等，计算得到。该力场的模拟精确度得到提高，随后将计算结果应用到其它RNA分子体系的测试。同时，测试结果显示我们的计算方法表现出了很好的可转移性。近3年，在项目资助下，我们新的用于RNA模拟的力场开发取得了很大的进展，共计发表SCI论文5篇，CCSD会议论文1篇。